Chronic and acute tolerance to nicotine reflects physiological or behavioral adaptation and may relate to the onset and persistence of smoking behavior, as well as to development of tobacco dependence. Litt1e research has examined tolerance to nicotine in humans, largely due to methodological problems in attempting to present reliable bolus doses of nicotine. This proposal is designed to investigate chronic and acute tolerance to cardiovascular (heart rate, systolic and diastolic blood pressure, pulse amplitude), subjective (self-reported arousla and symptoms), antinociceptive (lactencies to heat and pain thresholds during a thermal stimulus), and behavioral (handsteadiness and fingertapping task performance) responses to nicotine in humans. All studies will employa measured-dose nasal spray nicotine delivery procedure we have developed. Chronic tolerance will be determined by comparing responses of smokers vs. nonsmokers (i.e. subjects distinctly different in their past history of exposure to nicotine). To identify acute tolerance, responses to a "challenge" nicotine dose-response and time course effects of a single niicotine presentation in smokers vs. nonsmokers. Its aims will be to document differences in chronic tolerance and determine the optimum inter-dose interval for subsequent studies of acute tolerance. Study II will examine the effect of dose amount on acute tolerance in smokers and nonsmokers. Study III will vary the intrval between dose presentations to examine attenutation of acute tolerance. The last tow studies will focus on the environmental specificity of this nicotine tolerance. Study V will exmaine the conditioned effects of exposure to non-nicotine stimuli associated with smoking (e.g. sight, smell of smoke) on chronic and acute tolerance to nicotine. Results may proivde directions for the study of mechanisms responsible for tolerance, as well as for investigations of physiological and behavioral aspects of nicotine depenence and smoking relapse.